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• W4224034387 abstract "SUMMARY The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone protein secreted from mammalian cells. Stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions of destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent chaperoning activity. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction of destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases." @default.
• W4224034387 created "2022-04-19" @default.
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• W4224034387 date "2022-04-13" @default.
• W4224034387 modified "2023-09-27" @default.
• W4224034387 title "ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion Through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors" @default.
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• W4224034387 doi "https://doi.org/10.1101/2022.04.13.488200" @default.
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